Semelak, Jonathan A;
Gallo, Mariana;
Flecha, F Luis Gonzalez;
Di Pino, Solana;
Pertinhez, Thelma A;
Zeida, Ari;
Gout, Ivan;
... Trujillo, Madia; + view all
(2025)
Mg2+ binding to coenzyme A.
Archives of Biochemistry and Biophysics
, 763
, Article 110202. 10.1016/j.abb.2024.110202.
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Abstract
Magnesium (Mg<sup>2+</sup>), the second most abundant intracellular cation, plays a crucial role in cellular functions. In this study, we investigate the interaction between Mg<sup>2+</sup> and coenzyme A (CoA), a thiol-containing cofactor central to cellular metabolism also involved in protein modifications. Isothermal titration calorimetry revealed a 1:1 binding stoichiometry between Mg<sup>2+</sup> and free CoA under biologically relevant conditions. Association constants of (537 ± 20) M<sup>−1</sup> and (312 ± 7) M<sup>−1</sup> were determined at 25 °C and pH 7.2 and 7.8, respectively, suggesting that a significant fraction of CoA is likely bound to Mg<sup>2+</sup> both in the cytosol and in the mitochondrial matrix. Additionally, the process is entropically-driven, and our results support that the origin of the entropy gain is solvent-related. On the other hand, the combination of 1- and 2-dimensional nuclear magnetic resonance spectroscopy with molecular dynamics simulations and unsupervised learning demonstrate a direct coordination between Mg<sup>2+</sup> and the phosphate groups of the 4-phosphopantothenate unit and bound to position 5’ of the adenosine ring. Interestingly, the phosphate in position 3′ only indirectly contributes to Mg<sup>2+</sup> coordination. Finally, we discuss how the binding of Mg<sup>2+</sup> to CoA perturbates the chemical environment of different CoA atoms, regardless of their apparent proximity to the coordination site, through the modulation of the CoA conformational landscape. This insight holds implications for understanding the impact on both CoA and Mg<sup>2+</sup> functions in physiological and pathological processes.
| Type: | Article |
|---|---|
| Title: | Mg2+ binding to coenzyme A |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.abb.2024.110202 |
| Publisher version: | https://doi.org/10.1016/j.abb.2024.110202 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Biochemistry & Molecular Biology, Biophysics, BIOSYNTHESIS, Calorimetry, COA, Coenzyme A, Life Sciences & Biomedicine, Magnesium, MAGNESIUM-IONS, MAGNETIC-RESONANCE, MANGANESE, Mitochondria, MITOCHONDRIAL, Molecular dynamics, MOLECULAR-DYNAMICS, NMR, PERTURBATION, PYROPHOSPHATE, Science & Technology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217986 |
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